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Activation of the main DNA interstrand crosslink repair pathway in higher eukaryotes requires mono-ubiquitination of FANCI and FANCD2 by FANCL, the E3 ligase subunit of the Fanconi anemia core complex. FANCI and FANCD2 form a stable complex; however, the molecular basis of their ubiquitination is ill defined. FANCD2 mono-ubiquitination by FANCL is stimulated by the presence of the FANCB and FAAP100 core complex components, through an unknown mechanism. How FANCI mono-ubiquitination is achieved remains unclear. Here, we use structural electron microscopy, combined with crosslink-coupled mass spectrometry, to find that FANCB, FANCL, and FAAP100 form a dimer of trimers, containing two FANCL molecules that are ideally poised to target both FANCI and FANCD2 for mono-ubiquitination. The FANCC-FANCE-FANCF subunits bridge between FANCB-FANCL-FAAP100 and the FANCI-FANCD2 substrate. A transient interaction with FANCC-FANCE-FANCF alters the FANCI-FANCD2 configuration, stabilizing the dimerization interface. Our data provide a model to explain how equivalent mono-ubiquitination of FANCI and FANCD2 occurs., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

A dose escalating, placebo-controlled phase 1 trial was conducted to test the safety and immunogenicity of a vaccine containing recombinant Plasmodium falciparum apical membrane antigen 1 (AMA1) formulated in Montanide ISA720. Three groups of volunteers were vaccinated intramuscularly with 5 microg, 20 microg or 80 microg of AMA1, respectively, in 0.5 mL of formulation at 0, 3 and 6 months. Anti-AMA1 antibody levels and T cell stimulation indices were measured before and after each vaccination. No vaccine-related serious adverse events were recorded. Most subjects generated a mild to moderate, transient local reaction after the first vaccination. Three subjects developed a local reaction approximately 10 days following vaccination. Six of the 29 subjects seroconverted. Only one of these developed a high antibody titre. However, the interpretation of this trial was compromised by a loss of potency of the formulated vaccine during the course of the study.

The structures of bis(pyrazolylethyl) ether derivatives of zinc and cobalt, namely [eta(3)-O(CH(2)CH(2)pz(Pr)()i()2)(2)]Zn(NO(3))(2) and [eta(3)-O(CH(2)CH(2)pz(Me)()2)(2)]Co(NO(3))(2), have been determined with a view to addressing the applicability of such ligands in modeling bioinorganic aspects of zinc chemistry. Specific consideration is given to the possibility that bis(pyrazolylethyl) ether ligands may provide an NNO donor system which may model aspects of the binding of zinc to protein backbones in enzymes such as thermolysin. The structural studies demonstrate that the bis(pyrazolylethyl) ether ligands do indeed coordinate via each of their NNO functionalities but that the relationship to the enzyme is limited by the adoption of meridional rather than facial coordination geometries. [eta(3)-O(CH(2)CH(2)pz(Pr)()i()2)(2)]Zn(NO(3))(2) is monoclinic, P2(1)/c (No. 14), with a = 11.619(2) Å, b = 14.380(3) Å, c = 16.757(2) Å, beta = 90.44(2) degrees, and Z = 4. [eta(3)-O(CH(2)CH(2)pz(Me)()2)(2)]Co(NO(3))(2) is monoclinic, C2/c (No. 15), with a = 17.136(3) Å, b = 10.505(2) Å, c = 11.121(2) Å, beta = 104.62(3) degrees, and Z = 4.